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Fibroblast orchestration of the immune response in pancreatic cancer

胰腺癌免疫反应的成纤维细胞协调

基本信息

批准号：
10706561
负责人：
Howard C Crawford
金额：
$ 82.92万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-19 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10706561
关键词：
Address Affect African American Area Atlas of Cancer Mortality in the United States Biological Cancer Etiology Cells Cessation of life Characteristics Chemoresistance Classification Coculture Techniques Cytokine Gene Data Desmoplastic Diagnosis Disease Eligibility Determination Epithelium Ethnic Origin Evolution Excision Fibroblasts Gene Expression Profile Genes Genetic Transcription Genetically Engineered Mouse Growth Health system Heterogeneity Histologic Human Immune Immune response In Vitro Infiltration Inflammatory Investigation KRAS oncogenesis KRAS2 gene Ligands Literature Malignant Neoplasms Malignant neoplasm of pancreas Maps Mediating Mesenchymal Metabolic Michigan Minority Modeling Mus Mutation Nature Oncogenic Operative Surgical Procedures Organoids Pancreas Patients Population Predisposition Race Recurrence Regulation Role STAT3 gene Signal Pathway Signal Transduction Target Populations Testing Tumor Subtype Tumor Suppressor Proteins Tumor Volume Tumor-associated macrophages Tumor-infiltrating immune cells Universities Work advanced disease cancer cell cancer therapy carcinogenesis cytokine human disease in vivo molecular subtypes mutant neoplastic cell new therapeutic target novel therapeutic intervention pancreatic cancer model pancreatic cancer patients pancreatic tumorigenesis patient population programs racial population skills standard of care therapy resistant tumor

项目摘要

Pancreatic cancer is a deadly malignancy, direly in need of new therapeutic approaches. Pancreatic cancer is characterized by extensive accumulation of a fibroinflammatory stroma, containing abundant fibroblasts. Long believed to be a uniform cell population, fibroblasts have emerged as a heterogeneous and functionally important component of the tumor. Yet, the literature on fibroblasts in pancreatic cancer is controversial, with studies supporting both a pro- and an anti-tumor role. Our preliminary data show that oncogenic KRAS, a hallmark mutation of pancreatic cancer, expressed in tumor cells extrinsically reprograms the transcriptional program of fibroblasts. Further, continuous expression of epithelial oncogenic Kras is required to maintain expression of a panel of inflammatory cytokines in fibroblasts. Unlike mouse tumors, human pancreatic cancer is highly heterogeneous in terms of genetic alterations and histological characteristics of cancer cells. How fibroblasts are reprogrammed in the context of different types of human pancreatic cancer and how they contribute to carcinogenesis is unclear. Lastly, most in depth studies on pancreatic cancer are based on largely White patient populations, while the disease is equally prevalent in all race groups. The University of Michigan/Henry Ford Health System team together has access to a large patient volume, diverse patient populations (with 30% HFHS patients being African American), and the skillset to characterize and functionally assess fibroblasts on pancreatic cancer. We will map fibroblast heterogeneity across tumors in a diverse patient population. We will evaluate whether fibroblast heterogeneity correlates with different subtypes of tumor cells (classified as classical and mesenchymal). We will further take advantage of the genetically engineered mouse models available in our group to target fibroblast reprogramming at different stages of carcinogenesis. Overall, our work will shed light on the regulation and function of pancreatic CAFs and open the way for new therapeutic approaches targeting this population.

胰腺癌是一种致命的恶性肿瘤，迫切需要新的治疗方法。胰腺癌是其特征在于含有大量成纤维细胞的纤维炎性基质的广泛积累。长成纤维细胞被认为是均匀的细胞群，已经成为异质的和功能重要的细胞。肿瘤的组成部分。然而，关于胰腺癌成纤维细胞的文献存在争议，支持促肿瘤和抗肿瘤作用。我们的初步数据显示，致癌KRAS，一个标志性的胰腺癌的突变，在肿瘤细胞中表达，可对胰腺癌的转录程序进行外重编程，成纤维细胞此外，上皮致癌Kras的持续表达是维持癌基因表达所必需的。成纤维细胞中的一组炎性细胞因子。与小鼠肿瘤不同，人类胰腺癌高度在遗传改变和癌细胞的组织学特征方面，肿瘤细胞是异质的。成纤维细胞是如何在不同类型的人类胰腺癌的背景下重新编程，以及它们如何有助于致癌作用尚不清楚。最后，大多数关于胰腺癌的深入研究主要基于白色患者这一疾病在所有种族群体中同样普遍。密歇根大学/亨利福特卫生系统团队共同接触大量患者和不同患者人群（30% HFHS 患者为非裔美国人），以及表征和功能评估成纤维细胞的技能，胰腺癌我们将绘制不同患者人群中肿瘤间的成纤维细胞异质性。我们将评估成纤维细胞异质性是否与肿瘤细胞的不同亚型（分类为经典的和间充质）。我们将进一步利用基因工程小鼠模型，在不同阶段的癌发生中靶向成纤维细胞重编程。总的来说，我们的工作将揭示研究胰腺CAFs的调节和功能，为靶向治疗开辟新的途径，这个人口。